Comprehensive Overview of Tricyclic Antidepressants

This presentation provides a detailed study of Tricyclic Antidepressants (TCAs), covering their mechanism of action, pharmacokinetics, therapeutic uses, adverse effects, contraindications, and toxicity profile. It also compares TCAs with newer antidepressants to highlight their role in modern psychiatric and clinical practice.

1. Tricyclic Antidepressants By Nayab Fatima Roll No: 09

2. Contents Tricyclic Antidepressants Mechanism of action Pharmacokinetics Drug-drug interactions Drug–food interactions Therapeutic uses & ADRs Contraindications Drug doses

3. TCAs Tricyclic antidepressants are first-generation antidepressant drugs developed in the 1950s.They are called “tricyclic” because of their three-ring chemical structure.TCAs were once the mainstay treatment for depression before SSRIs and SNRIs were introduced.Though now less commonly used due to side effects, they are still valuable in chronic pain and anxiety management. Amitriptyline

4. Mechanism of action The primary mechanism of action for Tricyclic Antidepressants (TCAs) is the inhibition of the reuptake of the neurotransmitters serotonin (5-HT) and norepinephrine (NE) within the presynaptic terminals of nerve cells in the brain. ​This blockage of reuptake increases the concentration of these neurotransmitters in the synaptic cleft, which is thought to be the foundation of their antidepressant effect.

5. Mechanism of action Additionally, TCAs are known to have other pharmacological actions, including: ​ Antagonism of muscarinic cholinergic receptors (\text{M}_1), which contributes to common anticholinergic side effects like dry mouth and constipation. ​ Antagonism of histamine (\text{H}_1) receptors , which can lead to sedation and weight gain. ​ Antagonism of alpha-1 (\alpha_1) adrenergic receptors , which can cause orthostatic hypotension (dizziness when standing up).

6. Pharmacokinetics Absorption: Rapid & Extensive: TCAs are rapidly and well-absorbed from the gastrointestinal tract following oral dosing. ​First-Pass Effect: They undergo significant first-pass metabolism in the liver, which results in moderate systemic bioavailability (typically 40%-50%). ​ Highly Lipophilic: TCAs are very lipid-soluble, allowing them to cross the blood-brain barrier easily and enter tissues. ​High Protein Binding: They are highly bound to plasma proteins (up to 95\%). ​ Distribution

7. Pharmacokinetics Renal Clearance: The final metabolites are made water-soluble through hydroxylation and glucuronidation, and are then excreted primarily in the urine. ​ Long Half-Life: TCAs have relatively long elimination half-lives (typically 10 to 50 hours), allowing for once-daily dosing for many compounds. ​ Hepatic Metabolism: Metabolism occurs almost entirely in the liver . ​ Active Metabolites: Tertiary amines (e.g., Amitriptyline) are often converted into active secondary amine metabolites (e.g., Nortriptyline) via demethylation , which possess their own therapeutic effects. Metabolism: Excretion

8. Drug interactions TCAs + Monoamine Oxidase Inhibitors (MAOIs) Effect: Severe hypertension, hyperpyrexia, convulsions, or serotonin syndrome. Mechanism: Both increase monoamine (serotonin, norepinephrine) levels → toxic synergy . Example: Amitriptyline + Phenelzine → life-threatening reactions.Note: Maintain at least a 2-week gap between stopping an MAOI and starting a TCA. TCAs + CNS Depressants (Alcohol, Benzodiazepines, Antihistamines, Opioids ) Effect: Additive CNS depression → drowsiness, respiratory depression, confusion Mechanism: TCAs themselves have sedative properties via H₁ blockade.

9. TCAs + SSRIs : Effect: Increased TCA levels and risk of serotonin syndrome Result: Toxicity — confusion, tremors, cardiac arrhythmias. Drug –drug interactions

10. Drug-food interactions 1. Food and Absorption Effect: Food slightly delays absorption of TCAs but does not reduce overall bioavailabili ty. 2. Alcohol (Ethanol ) Effect: Additive CNS depression — drowsiness, dizziness, impaired coordination, and confusion. Mechanism: Alcohol and TCAs both depress CNS activity. Recommendation: Avoid alcohol completely during TCA therapy. 3. Caffeine (Tea, Coffee, Energy Drinks) Effect: Reduced sedative effect of TCAs and possible increase in anxiety or insomnia .Mechanism: Caffeine is a CNS stimulant that counteracts the sedative effects of TCAs. Advice: Limit caffeine intake.

11. Contraindications R ecent myocardial infarction C ardiac conduction defects Li ver diseas e Gla ucoma U rinary retention P rostatic hypertrophy E pilepsy, bipolar mania MAOI therapy C hildren or elderly with high sensitivity to CNS effe cts Tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline are effective antidepressants but have several important contraindications due to their potent effects on the cardiovascular, neurological, and autonomic systems.

12. Examples Tertiary amines: Amitriptyline Imipramine Trimipramine Clomipramine Desipramine Nortriptyline Protriptyline Secondary amines

13. Doses

14. Conclusion Tricyclic antidepressants are effective mood-elevating drugs that act by blocking norepinephrine and serotonin reuptake.However , they cause many side effects (sedation, anticholinergic, and cardiac toxicity) and have serious drug interactions, limiting their clinical use.They are now mainly used when newer antidepressants fail or for pain and migraine management.

15. References Katzung, B. G., et al. Basic & Clinical Pharmacology, 16th Edition, McGraw-Hill Education. Rang, H. P., Dale, M. M., et al. Rang and Dale’s Pharmacology, 9th Edition, Elsevier. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 14th Edition.